Hypervigilance and Anxiety are Elevated Among Patients With Laryngeal Symptoms With and Without Laryngopharyngeal Reflux
Authors: Amanda Jayne Krause, Madeline Greytak, Zoe C. Burger, Tiffany Taft, Rena Yadlapati
Journal: Clinical Gastroenterology and Hepatology (2022)

Most patients experiencing laryngeal symptoms are labeled as having laryngopharyngeal reflux (LPR).1Yadlapati R. et al.Clin Gastroenterol Hepatol. 2022; 20: 776-786Google Scholar LPR has classically been defined as an extraesophageal manifestation of gastroesophageal reflux disease (GERD) in which gastric refluxate leads to irritation of and increased nociception at the upper aerodigestive tract.2Katz P.O. et al.Am J Gastroenterol. 2022; 117: 27-56Google Scholar Diagnosis of LPR poses a significant challenge to clinicians and patients. For instance findings on laryngoscopy graded according to the validated reflux finding score are nonspecific for LPR because multifactorial etiologies including postnasal drip or allergies can result in an elevated reflux finding score.2Katz P.O. et al.Am J Gastroenterol. 2022; 117: 27-56Google Scholar Similarly, patient-reported symptoms as measured by several validated instruments (eg, Reflux Symptom Index) have poor prognostic performance in predicting laryngeal symptom response.3Wilson J.A. et al.Health Technol Assess. 2021; 25: 1-118Google Scholar Because not all laryngeal symptoms are driven by acidic refluxate, hence often not responsive to traditional antireflux therapies, current guidelines and best practice updates recommend ambulatory reflux monitoring off acid suppression in patients with isolated LPR symptoms before a trial of proton pump inhibitor therapy.2Katz P.O. et al.Am J Gastroenterol. 2022; 117: 27-56Google Scholar Furthermore, a recent study demonstrated that patients with laryngeal symptoms present with distinct phenotypes (eg, LPR/GERD, LPR/hypersensitivity, no LPR/no GERD), among which cognitive-affective processes may drive symptom burden to varying degrees across phenotypes.1Yadlapati R. et al.Clin Gastroenterol Hepatol. 2022; 20: 776-786Google Scholar This notion that cognitive-affective processes impact symptom severity and quality of life in the realm of typical GERD is increasingly accepted, and consequently gut-directed behavioral therapies are recommended across the spectrum of GERD.4Guadagnoli L. et al.Neurogastroenterol Motil. 2021; 33e14081Google Scholar Furthermore, the validated esophageal hypervigilance and anxiety scale (EHAS) patient report instrument assesses levels of symptom-associated anxiety and hypervigilance.5Taft T.H. et al.Aliment Pharmacol Ther. 2018; 47: 1270-1277Google Scholar One such questionnaire, the Newcastle Laryngeal Hypersensitivity Questionnaire, was validated for LPR; however, unlike the EHAS, it focuses on symptoms rather than the impact of cognitive-affective processes on symptom perception.6Vertigan A.E. et al.Cough. 2014; 10: 1Google Scholar Unfortunately, the current paradigm for LPR largely ignores the interplay of psychological stressors on symptom burden.7Krause A.J. et al.Ann N Y Acad Sci. 2022; 1510: 5-17Google Scholar This dearth of research in the role of psychological stressors and behavioral therapy is a tremendous missed opportunity to help patients with chronic laryngeal complaints. To address this knowledge gap, we aimed to measure hypervigilance and anxiety in patients with laryngeal symptoms and compare hypervigilance and anxiety levels between symptomatic patients with and without LPR. This single center observational study enrolled patients over 2 years (September 2019–September 2021). Patients were included if they were adults with laryngeal symptoms (cough, dysphonia, throat clearing, sore throat, mucous in throat, globus) that underwent ambulatory reflux monitoring off acid suppression and completed the EHAS. Patients were defined as having true LPR if acid exposure time (AET) on reflux monitoring was ≥6% (LPR+) and no LPR if AET <6% (LPR-). The study was approved by the institutional review board. See the Supplementary Methods for more information. A total of 77 patients are included in the analysis: mean age was 49.8 years (standard deviation [SD], 15.3) and 60 (78%) were female. Twenty-two (29%) met criteria for LPR+ (mean AET, 13.1% [11.7]) and 55 (71%) met criteria for LPR- (mean AET, 1.7 [1.6]). (Table 1). Mean body mass index was significantly higher in the LPR+ versus LPR- group (28.0 [6.4] vs 24.7 [4.1]; P = .01). There were no significant differences between age, sex, and Gastroesophageal Reflux Questionnaire or Reflux Symptom Index scores between groups.Table 1Patient CharacteristicsLPR- (AET <6%), n = 55LPR+ (AET ≥6%), n = 22P valueAge, y49.8 (SD, 15.8)49.8 (SD, 14.3).99Female sex46 (84%)14 (64%).06Body mass index, kg/m224.7 (SD, 4.1)28.0 (SD, 6.4).01Esophageal AET, %1.7 (SD, 1.6)13.1 (SD, 11.7)< .001GerdQ score7.2 (SD, 3.2), n = 548.6 (SD, 3.5), n = 21.09Reflux symptom index score19.1 (SD, 9.2)20.9 (SD, 8.2).43EHAS total33.2 (SD, 14.9)35.0 (SD, 12.8).62EHAS Q1–9 (anxiety domain)20.5 (SD, 10.1)20.5 (SD, 9.5).99EHAS Q10–15 (hypervigilance domain)12.7 (SD, 5.9)14.5 (SD, 5.6).22Elevated EHAS score (>21)45 (82%)19 (86%).63NOTE. Depicted as mean (SD) for continuous variables or n (%) for categorical variables.AET, acid exposure time; EHAS, esophageal hypervigilance and anxiety scale; GerdQ, Gastroesophageal Reflux Questionnaire; LPR, laryngopharyngeal reflux; SD, standard deviation. Open table in a new tab NOTE. Depicted as mean (SD) for continuous variables or n (%) for categorical variables. AET, acid exposure time; EHAS, esophageal hypervigilance and anxiety scale; GerdQ, Gastroesophageal Reflux Questionnaire; LPR, laryngopharyngeal reflux; SD, standard deviation. A similarly high proportion of patients in both groups reported elevated EHAS scores (45 [82%] LPR- and 19 [86%] LPR+; P = .63). Mean total EHAS scores were similar in the LPR- and LPR+ groups (33.2 [SD, 14.9] vs 35.0 [SD, 12.8]; P = .62). EHAS-anxiety and EHAS-hypervigilance subscores were not significantly different between LPR- and LPR+ groups (Supplementary Figure 1). There was no difference in EHAS score between the LPR- and LPR+ groups (odds ratio, 1.01; 95% confidence interval, 0.97–1.05; P = .67), which was maintained in a multivariable regression model adjusting for sex, body mass index, and Gastroesophageal Reflux Questionnaire score (odds ratio, 1.01; 95% confidence interval, 0.97–1.05; P = .67). Similar patterns were noted in the sensitivity analysis where an AET cutoff of 4% was used to categorize LPR+/LPR- groups (Supplementary Table 1). In summary, individuals with laryngeal symptoms represent a heterogenous group with varying symptoms and pathologies, and often pose a challenge for clinicians. In this study of 77 patients with laryngeal symptoms, less than one-third met criteria for true LPR, highlighting that a significant portion of patients with laryngeal symptoms presenting for evaluation do not have concomitant GERD, and are unlikely to benefit from reflux-targeted therapies. Furthermore, both groups with and without true LPR reported elevated levels of hypervigilance and anxiety, suggesting that cognitive-affective processes are interrelated with laryngeal symptom burden regardless of reflux physiology, and may represent an important therapeutic target. The concepts of cognitive-affective processes driving or contributing to esophageal symptom burden, rather than solely pathologic reflux events, is well accepted in GERD.8Kahrilas P.J. et al.Neurogastroenterol Motil. 2015; 27: 1195-1201Google Scholar These functional esophageal disorders are noteworthy because they are poorly understood and can have implications in patient quality of life and health care utilization.7Krause A.J. et al.Ann N Y Acad Sci. 2022; 1510: 5-17Google Scholar As such a pillar of treatment in GERD aims to target these processes with stress reduction, pharmacologic neuromodulation, and gut-directed behavioral therapy.9Katzka D.A. et al.Clin Gastroenterol Hepatol. 2020; 18: 767-776Google Scholar Although the concept of a functional laryngeal disorder has been proposed, there is a dearth of data to support and guide management.10Patel D.A. et al.Gastroenterol Hepatol (N Y). 2018; 14: 512-520Google Scholar Some researchers propose laryngeal hyperresponsiveness could be caused by an exaggerated response to stimuli, in that certain patients are more sensitive to certain laryngeal sensations.10Patel D.A. et al.Gastroenterol Hepatol (N Y). 2018; 14: 512-520Google Scholar Our study is the first to identify elevated levels of hypervigilance in patients with and without true LPR, suggesting a physiopsychological interplay of factors that modulate symptom burden in LPR and highlighting the potential of integrative treatment approaches beyond reflux-targeted therapy. Future studies evaluating response to behavioral and speech treatments directed at cognitive-affective processes are needed. Furthermore, a validated patient report instrument to measure laryngeal symptom-specific hypervigilance and anxiety will be of value rather than reliance on the EHAS. Strengths of the study include that all patients were well-characterized on the basis of their reflux monitoring data, rather than reliance on presence of symptoms alone. Limitations include the observational nature of the study without outcomes data. In conclusion, this study highlights that most patients presenting with laryngeal symptoms do not have pathologic GERD and suggests that therapies targeting cognitive-affective processes are an essential component of treatment, regardless of their physiologic acid exposure burdens. The validated 15-item EHAS patient-reported instrument includes questions 1–9 focused on anxiety and 10–15 focused on hypervigilance; cumulative scores >21 are considered significant. Patients also completed the Gastroesophageal Reflux Questionnaire (GerdQ), which is a 6-item questionnaire with scores of ≥8 suggestive of reflux, and the Reflux Symptom Index, a 9-item questionnaire with scores of ≥13 suggestive of LPR. Ambulatory reflux monitoring included 24-hour impedance-pH monitoring or 96-hour wireless pH monitoring (Medtronic, Minneapolis, MN). Patients were defined as having true LPR if AET on reflux monitoring was ≥6% (LPR+) and no LPR if AET <6% (LPR-). Two-sample t-test compared continuous total and sub-EHAS scores and chi-square test compared proportion of patients with EHAS >21 between LPR+ and LPR- groups. A sensitivity analysis considered an AET threshold of 4.0% to define LPR+ or LPR-. Finally, a multivariable regression model assessed EHAS score, sex, body mass index, and GerdQ score. P < .05 was considered statistically significant. Statistical analyses were run using STATA 14 (StataCorp, Houston, TX).Supplementary Table 1Patient CharacteristicsAET <4%, n = 48AET ≥4%, n = 29P valueAge, y49.4 (SD, 15.7)50.4 (SD, 14.8).79Female sex39 (81%)21 (72%).37Body mass index, kg/m224.5 (SD, 4.1)27.6 (SD, 5.9).01Esophageal AET, %1.3 (SD, 1.0)11.2 (SD, 10.7)< .001GerdQ score7.2 (SD, 3.1), n = 488.3 (SD, 3.7), n = 27.19Reflux symptom index score18.9 (SD, 9.4)20.9 (SD, 8.1).33EHAS total33.9 (SD, 13.7)33.4 (SD, 15.6).89EHAS Q1–9 (anxiety domain)20.9 (SD, 9.3)19.9 (SD, 10.8).69EHAS Q10–15 (hypervigilance domain)13.0 (SD, 5.5)13.5 (SD, 6.5).74Elevated EHAS score (>21)41 (85%)23 (79%).49NOTE. Depicted as mean (SD) for continuous variables or n (%) for categorical variables.AET, acid exposure time; EHAS, esophageal hypervigilance and anxiety scale; GerdQ, Gastroesophageal Reflux Questionnaire; LPR, laryngopharyngeal reflux; SD, standard deviation. Open table in a new tab NOTE. Depicted as mean (SD) for continuous variables or n (%) for categorical variables. AET, acid exposure time; EHAS, esophageal hypervigilance and anxiety scale; GerdQ, Gastroesophageal Reflux Questionnaire; LPR, laryngopharyngeal reflux; SD, standard deviation.